Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior. Glucocorticoids such as cortisol control carbohydrate, fat and protein metabolism and are anti-inflammatory by preventing phospholipid release, decreasing eosinophil action and a number of other mechanisms. Mineralocorticoids such as aldosterone control electrolyte and water levels, mainly by promoting sodium retention in the kidney. Some common natural hormones are corticosterone, cortisone, 17-hydroxy-11-dehydrocorticosterone and aldosterone.
Aldosterone is mainly produced in the adrenal cortex, where its biosynthesis from the precursor cholesterol involves a number of catalytic steps and enzymes. The early steps of aldosterone biosynthesis share pathways and precursors with other steroidal hormones. The final steps of aldosterone biosynthesis are conducted by the cytochrome P450 enzymes 11B1 (cortisol synthase or steroid-11μ-hydroxylase) and 11B2 (aldosterone synthase), which will further be denoted as CYP11B1 and CYP11B2, respectively. These enzymes catalyze the 11-hydroxylation of 11-deoxycorticosterone to corticosterone, which is then further hydroxylated by CYP11B2 to 18-hydroxycorticosterone (18OH—B). Finally, CYP11B2 (but not CYP11B1) oxidizes the 18-hydroxyl group of 18OH—B to the corresponding aldehyde, thus resulting in the formation of aldosterone.
CYP11B1, however, is also involved in the biosynthesis of cortisol (hydrocortisone). Specifically, it catalyzes the conversion from 11-deoxycortisol to cortisol, i.e. the key reaction in cortisol biosynthesis. Cortisol is the main glucocorticoid in humans. It regulates energy mobilization and thus the stress response. In addition, it is involved in the immune response of the human body. Abnormally increased Cortisol level is the cause of a variety of diseases including Cushing's syndrome.
Endogenous Cushing's syndrome is a hormonal disorder caused by prolonged exposure to excessive levels of circulating glucocorticoids, therefore also called hypercortisolism. Signs and symptoms of this disorder vary, but most people develop central obesity, a round face and very often also diabetes and hypertension. Cushing's syndrome is the cause of considerable morbidity and mortality. In about 80% of all cases a pituitary hypersecretion of ACTH is observed, which is mostly related to an ACTH-secreting pituitary adenoma (Cushing's disease). Benign or malignant adrenocortical tumors are the most common reasons for ACTH-independent hypercortisolism. The standard treatment for most patients is the surgical removal of the tumor or radiation therapy. However, a third of all patients are not treatable with these therapies and require temporary or permanent medication. Therefore, the application of drugs lowering the elevated cortisol levels or reducing glucocorticoid activity is considered as method of choice.
However, results with the glucocorticoid receptor antagonist mifepristone show, that administration of these agents triggers a massive secretion of cortisol which is probably caused by the hypothalamic pituitary feedback mechanism. A decrease of glucocorticoid formation should be a better therapeutic option. The best target for such an approach is steroid-11β-hydroxylase (CYP11B1), an adrenal CYP enzyme which directly affects cortisol production by catalyzing the final step in cortisol biosynthesis, namely hydroxylation of deoxycortisol in 11β-position (FIG. 1).
A major problem in the development of CYP enzyme inhibitors is the selectivity versus other CYP enzymes. Aromatase (estrogen synthase, CYP19) and 17α-hydroxylase-C17,20-lyase (CYP17) inhibitors are first line drugs for the treatment of breast cancer and upcoming therapeutics for castration refractory prostate cancer, respectively. In case of adrenal CYP11B enzymes matters are much more challenging as the homology between CYP11B1 and CYP11B2 is very high (93%) (Mornet et al. J. Biol. Chem. 1989, 264, 20961-20967) and for a long time it was considered impossible to obtain selective inhibitors.
Nevertheless, CYP11B1 is the key enzyme in cortisol biosynthesis and its inhibition with selective compounds is a promising strategy for the treatment of diseases associated with elevated cortisol levels like Cushing's syndrome or metabolic disease which are otherwise not appropriately treatable.
Until recently, selective inhibitors of mineralo- and glucocorticoids were not in the focus of research efforts. This was due to the fact that the sequence identity between aldosterone synthase (CYP11B2) and cortisol synthase (steroid-11μ-hydroxylase, CYP11B1) is very high (93%), and it was considered impossible to obtain selective inhibitors of one enzyme versus the other. Thus, although there is a high medical need for drugs interfering with excessive glucocorticoid formation resulting, for example, in Cushing's syndrome, there are only few inhibitors of CYP11B1 described so far. Because of their unselective action, their application is associated with severe side effects: The CYP19 inhibitor aminoglutethimide, metyrapone, the antimycotics ketoconazole and fluconazole, and the hypnotic etomidate are also inhibitors of other adrenal and gonadal Cytochrom P450 (CYP) enzymes. However, all of them show severe side effects due to the fact that they are unselective, i.e. they inhibit a broad range of CYP enzymes or hydroxysteroid dehydrogenases (HSDs). Some common side effects include gastrointestinal upset, edema, rash, malaise, gynecomastia and elevated transaminases (see Contemporary Endocrinology: Diagnosis and management of Pituitary Disordwers, Ed. By: Swearingen and Biller, Humana Press (2008), Totowa, N.J.).
Accordingly, the hypnotic and unselective CYP inhibitor etomidate was recently used as starting point in several drug discovery programs. While Roumen et al. (J. Med. Chem. 2010, 53, 1712-1725) discovered selective CYP11B2 inhibitors outgoing from etomidate and fadrozole, Zolle et al. (J. Med. Chem. 2008, 51, 2244-2253) described etomidate derived CYP11B1 inhibitors without investigating selectivity toward other CYPs. Also, WO 2007/139992 describes both CYP11B2 and CYP11B1 inhibitors based on imidazole derivatives. However, it does not provide selective CYP11B1 inhibitors.
Jagusch et al. (Bioorg. Med. Chem. 16 (2008) 1992-2010) discloses imidazole based molecules as substrate mimetic of CYP17 (an enzyme involved in the biosynthesis of androgen) that are useful in the treatment of prostate cancer.
PCT patent application publication number WO02/060877 discloses imidazole derivative which are NMDA (N-methyl-D-aspartate) receptor subtype 2B selective blockers which have as possible therapeutic indications acute forms of neurodegeneration caused, e.g., by stroke and brain trauma, and chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis) and neurodegeneration associated with bacterial or viral infections, and, in addition, depression and chronic and acute pain.